Cytokines a bridge between the nervous system and the immune system

Cytokines are cell-derived peptides that may modify the functions of the cells that secrete them, as well as the functions of other cells that have receptors for them. Table 2 lists a number of cytokines that are produced and act in both the nervous system and the immune system.

Some of our initial knowledge of cytokines that are produced by cells outside the nervous system but that have an apparent effect within the nervous system came from clinical observations. One early study demonstrated that during an acute phase response to a systemic bacterial infection, the associated fever and transient accumulation of inflammatory cells in the central nervous system (CNS) are mediated by IL-1 and IL-6. In addition, numerous anecdotal clinical observations pointed to effects of IL-2, interferon 7 (IFNy), tumor necrosis factor a (TNFa), and transforming growth factor |3 (TGFfi) on the nervous system, even though these cytokines may be synthesized by cells outside of the nervous system.

Initially, many investigators sought pathways by

Table 1 Neuromediators and their effects on immunity

Neuromediator

Effect on Effect on humoral cellular immunity immunity

Neurotransmitters

Epinephrine

Norepinephrine

Dopamine

Serotonin

Acetylcholine

Histamine

Neuropeptides

Enkephalins

Adrenocorticotropic hormone (ACTH)

Growth hormone

Prolactin

Somatostatin

Vasoactive Intestinal peptide (VIP) Substance P

Calcitonin gene-related peptide Nerve growth factor

" Much of what is known about these effects is derived from in vitro systems; a number of the neuromediators exhibit concentration-dependent effects on immunity and thus characterization of enhancement (Î) or suppression (J) of a response depends on the conditions of the experiment.

which exogenously-produced cytokines could be transported into the CNS. Although such pathways have now been identified and the circumstances under which the blood-brain barrier is sufficiently compromised to allow cytokines to pass from the blood into the CNS are known, it has also been shown that these pathways are not the only means by which these mediators come to be present in the brain. A number of years ago, it was demonstrated that IL-1 and IL-6 are produced by cells in the pituitary gland and that IL-1 may be the regulator of IL-6 production by these cells. Given the knowledge that these two cytokines are mediators of inflammatory reactions and that one or both can stimulate the production of glucocorticoids by the adrenal gland, it became obvious that nervous system-derived cytokines, including the interleukins, could be a dircct link between the nervous system and the immune system.

Since these early observations were made, the literature regarding cytokine production and cyto-kine-producing cells in the nervous system has burgeoned. It is now known that astrocytes and microglial cells are sources of IL-1, IL-6, TNFa, colony-stimulating factor and TGFfJ, as well as a host of other chemokines whose structures and functions are now being clarified. More recently it has been shown that oligodendrocytes can also produce IL-1 and TGF(3. The fact that astrocytes and microglial cells produce these cytokines in response to a variety of stimuli has caused some investigators to speculate that these cells represent an arm of the immune system within the nervous system. Certainly, the production of IL-1 and IL-6, as well as TNFa, by astrocytes and microglial cells makes a strong case for the role of these mediators within the nervous system in the regulation of proliferation, differentiation and the cellular response to infectious agents and injury as part of the effort to promote survival of the organism (Figure 8).

The link between the nervous system and the immune system is evident from the fact that nervous system-derived cytokines and chemokines act on immune cells outside the system. Thus, IL-1 and IL-6 produced by microglial cells and astrocytes may act on immune cells outside the nervous system and certainly can act on lymphocytes and macrophages that enter the nervous system during infectious processes. There is evidence that lymphocytes and antigen-presenting cells accumulate at sites of herpes virus infections in both the peripheral and the central nervous system; it seems likely that the mediators necessary both to promote the attraction of these immune system cells and to promote and enhance their immune function within the nervous system are

Table 2 Cytokines that act in both the nervous system and the immune system

Cytokine

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